Implantable silicon microelectrode array technology is a promising approach for high-density, high-resolution sampling of neuronal activity with application in both basic research and prosthetic devices. One of the major limitations of the current technology is inconsistent performance in long-term applications, which limits clinical development. Although the brain tissue response to implanted electrodes is believed to be a major cause of electrical instability, the precise mechanisms that cause failure of recordings are not known. Understanding the mechanisms that underlie chronic instability of silicon microelectrode arrays will, therefore, lead to strategies to improve their usefulness for chronic basic science studies and various neuroprosthetic applications. We have observed persistent ED-1 immunoreactivity around silicon microelectrode arrays implanted in the adult rat motor cortex, and observed significant reductions in nerve fiber density and cell bodies in the tissue immediately surrounding implanted silicon microelectrode arrays. Persistent ED-1 up-regulation and neurodegeneration is not observed in microelectrode stab controls indicating that chronic inflammation and neuronal loss is not caused by the initial mechanical trauma of electrode implantation, but is associated with the brain tissue response to the implanted electrode. We find that our observations share biological features of diseases having a neuroinflammatory mediated neurotoxic component. We, therefore, hypothesize that chronically implanted silicon microelectrode arrays lead to persistent macrophage activation at the microelectrode interface resulting in an over production of proinflammatory cytokines and neurotoxic factors that lead to loss of neuronal cell bodies and fibers immediately adjacent to the recording surface. To test our hypothesis, quantitative methods are proposed: a) to determine the temporal histopathological changes at the microelectrode brain tissue interface that coincide with recording failure; in addition 2) we will determine the changes in proinflammatory and neurotoxic factors at the implant site using retrieved probes and a new system that allows sampling of the institial fluid adjacent to the implant over time; and, finally c) we will test the hypothesis that agents that interfere with microglial activation and signaling are effective in attenuating neurodegeneration around the implanted silicon microelectrode arrays. The proposed research is likely to provide insight into the biological mechanisms that underlie chronic instability of silicon microelectrode arrays, and should lead to strategies to improve their usefulness for chronic applications.